Role of PDK1 in pancreatic cancer cell fitness under tumor nutrient stress
PDK1在肿瘤营养应激下胰腺癌细胞健康中的作用
基本信息
- 批准号:10751747
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-30 至 2025-09-29
- 项目状态:未结题
- 来源:
- 关键词:AffectAnabolismAnimalsBiochemicalBiological AssayBiological MarkersBiological ModelsBlood VesselsCRISPR interferenceCRISPR screenCarbonCell SurvivalCellsCitric Acid CycleClinicCommunicationDataDependenceDiseaseDrug CompoundingEnvironmentEquilibriumFermentationFormulationGeneticGoalsGrowthHomeostasisHypoxiaInjectionsIntercellular FluidLactic acidLipidsMalignant neoplasm of pancreasMediatingMediatorMetabolicMetabolismModelingMusNADHNucleic AcidsNutrientNutrient availabilityOxidation-ReductionOxidative StressOxygenPDH kinasePancreatic Ductal AdenocarcinomaPathway interactionsPerfusionPhosphorylationPhosphotransferasesProductionProliferatingProteinsProto-Oncogene Proteins c-aktPyruvatePyruvate Dehydrogenase ComplexReactive Oxygen SpeciesRegulationRoleSignal PathwaySignal TransductionStressTestingTherapeutically TargetableTissuesWorkaerobic glycolysiscancer cellcancer typecell growthclinical translationclinically relevantcofactorcytotoxiceffective therapyfitnessin vivoknock-downmacromoleculemetabolic abnormality assessmentmetabolomicsneoplastic cellnormoxianovelnovel therapeutic interventionoxidationpancreatic cancer cellspancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpreventpyruvate dehydrogenaseresponsescreeningsensortherapeutic targettumortumor growthtumor microenvironment
项目摘要
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type in urgent need of more
effective treatment options. A notable feature of PDAC tumors is the highly altered nutrient conditions present
within the tumor microenvironment (TME) caused by poor perfusion from the supporting tumor vasculature.
Although PDAC cells can rapidly proliferate within these suboptimal nutrient conditions, the metabolic
adaptations they rely upon to do so remain unknown. Furthermore, understanding these adaptations has the
potential to reveal therapeutically targetable vulnerabilities of PDAC cells in vivo. Towards this end, we have
developed a novel medium formulation (TIFM) that recapitulates the nutrient conditions present within PDAC
tumors in vivo, in order to study the metabolic responses of PDAC cells to tumor nutrient stress using tractable
ex vivo models. Applying pooled CRISPR-interference (CRISPRi) screening to this new model system, we
surprisingly identified a hypoxia-induced kinase, pyruvate-dehydrogenase kinase 1 (PDK1), as being critical to
the fitness of PDAC cells in TIFM, even under normoxia conditions. PDK1 is a kinase normally activated by
hypoxia to inhibit the pyruvate dehydrogenase (PDH) complex and thus redirect pyruvate-derived carbon away
from the TCA cycle and towards lactic acid fermentation. The overall goal of this proposal is to understand how
and why PDK1 and aerobic glycolysis become critical to PDAC cellular fitness during tumor nutrient stress, and
to evaluate in vivo the functional dependence of PDAC cells on suppressed pyruvate oxidation for tumor
growth. I hypothesize that two potential mechanisms may underlie PDK1 dependency in TIFM: (1) PDK1
promotes aerobic glycolysis to prevent the production of cytotoxic levels of reactive oxygen species (ROS) or
(2) supports NAD+/NADH cofactor balance for macromolecule biosynthesis. Further, I hypothesize that PDK1
activity is upregulated under TIFM conditions through a nutrient-sensitive mTORC2-AKT-PDK1 signaling axis.
We will investigate this hypothesis in three specific aims. Aim 1. Functional and metabolic assays will be
performed to determine the adaptive function of PDK1 under tumor nutrient stress. Aim 2. Functional and
biochemical assays will be performed to identify the nutrient factor in TIFM responsible for PDK1 dependency
and elucidate the signaling pathway that communicates its availability to the TCA cycle. Aim 3. Animal studies
will be performed to determine the essentiality of suppressed pyruvate oxidation for PDAC tumor growth in
vivo. These findings reveal a critical metabolic dependency of cancer cells in adaptation to the nutrient stress
present in the TME. Furthermore, understanding this adaptation may reveal novel therapeutic strategies for
managing pancreatic cancer in the clinic based on metabolic constraints set by the tumor microenvironment.
项目总结
项目成果
期刊论文数量(0)
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